PTAB

IPR2025-00427

Azurity Pharmaceuticals Inc v. Exelixis Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Pharmaceutical Compositions of Cabozantinib
  • Brief Description: The ’039 patent relates to oral pharmaceutical compositions (tablets or capsules) of cabozantinib (L)-malate and methods of treating cancer using them. The claims require that the composition contains 100 parts per million (ppm) or less of a specific impurity, 6,7-dimethoxy-quinoline-4-ol.

3. Grounds for Unpatentability

Ground 1: Claims 1-22 are obvious over Brown in view of Kubo.

  • Prior Art Relied Upon: Brown (WO 2010/083414) and Kubo (Patent 7,169,789).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Brown disclosed all elements of the challenged claims except for the specific impurity concentration limit. Brown taught cabozantinib (L)-malate, formulating it into tablets and capsules with pharmaceutically acceptable carriers, and using these compositions to treat the specific cancers recited in the dependent claims (renal, prostate, hepatocellular). Petitioner contended that Brown's disclosed synthesis route for cabozantinib (L)-malate produces the active pharmaceutical ingredient (API) with "at most, de minimis" levels of the 6,7-dimethoxy-quinoline-4-ol impurity. The only transformative difference between the synthesis in Brown and that described in the ’039 patent is Brown's use of a two-step reaction versus the patent’s one-step reaction to form a key intermediate. Kubo expressly taught performing this exact transformation using a one-step "alternative" approach.
    • Motivation to Combine: A POSITA would combine Kubo's teaching with Brown's synthesis for clear benefits of efficiency and economy. Kubo's one-step method was superior, offering significantly higher yields (e.g., 92% vs. 28% in an analogous reaction), reducing the number of synthetic steps, eliminating hazardous reagents, and simplifying product purification. These advantages provided a strong motivation to substitute Kubo’s efficient one-step process into Brown’s overall synthesis of cabozantinib (L)-malate.
    • Expectation of Success: Petitioner asserted a POSITA would have had a high expectation of success. The single-step reaction taught by Kubo was known to be effective for the same class of compounds and produced the same intermediate as Brown's two-step process. Applying this more efficient synthesis to Brown's process would be expected to further reduce the already "de minimis" impurity levels, inherently resulting in a final product meeting the claimed <100 ppm concentration. Petitioner argued the claimed impurity ranges are an inherent property of the obvious combination.

Ground 2: Claims 1-22 are obvious over Brown in view of Robinson.

  • Prior Art Relied Upon: Brown (WO 2010/083414) and Robinson (a 2010 review article titled “Control of Genotoxic Impurities in Active Pharmaceutical Ingredients”).
  • Core Argument for this Ground:
    • Prior Art Mapping: As in Ground 1, Brown taught preparing a cabozantinib (L)-malate composition containing a "de minimis" amount of the 6,7-dimethoxy-quinoline-4-ol impurity. Petitioner argued that the quinoline structure of this impurity was a known "structural alert" for potential genotoxicity. Robinson explained that regulatory guidelines require developers to identify and control such potentially genotoxic impurities (PGIs) to concentrations below a "threshold of toxicological concern." For the known dosages of cabozantinib disclosed in the art, this threshold would correspond to a concentration limit below 120 ppm, directly overlapping with the claimed ranges.
    • Motivation to Combine: A POSITA developing the cabozantinib composition from Brown for commercialization would be compelled by standard drug development practices and regulatory requirements, as detailed by Robinson, to address the potential genotoxicity of the known impurity. This would motivate the POSITA to identify the impurity's presence and reduce its concentration to a level of safety, which Robinson taught was a routine and required step in pharmaceutical development.
    • Expectation of Success: A POSITA would have had a high expectation of successfully reducing the impurity to the claimed levels. Robinson described that the pharmaceutical industry routinely used established methods, such as chromatography (a technique Brown itself disclosed for monitoring), to reduce PGIs to the required ppm levels. Achieving the claimed impurity concentrations was not an inventive step but rather an expected and necessary outcome of standard pharmaceutical development and purification protocols.

4. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under Fintiv would be inappropriate because there was no pending parallel litigation between Azurity and Exelixis. Petitioner further argued that even if the Board were to consider a concluded district court case involving Exelixis and a third party (MSN) concerning a related patent, denial would still be improper. The grounds presented in this petition are different from those in the prior litigation, relying on new combinations of prior art (specifically, the Kubo and Robinson references), and Petitioner was not a party to that litigation. Petitioner also contended that under Advanced Bionics, the obviousness arguments here were not substantially the same as those presented to the examiner during prosecution, who rejected the claims based only on anticipation and double patenting.

5. Relief Requested

  • Petitioner requested institution of an inter partes review and cancellation of claims 1-22 of Patent 12,128,039 as unpatentable under 35 U.S.C. §103.